Basic Neurochemistry (eBook)

Basic Neurochemistry 3
Basic Neurochemistry 5
Contents 7
Section Editors 11
Contributors 13
Acknowledgments and History 21
Preface to the Seventh Edition 23
Pierre Morell, Ph.D. 1941–2003 25
Cellular Neurochemistry and Neural Membranes 27
Neurocellular Anatomy 29
UNDERSTANDING NEUROANATOMY IS NECESSARY TO STUDY NEUROCHEMISTRY 29
CHARACTERISTICS OF THE NEURON 30
CHARACTERISTICS OF NEUROGLIA 37
ACKNOWLEDGMENTS 44
REFERENCES 44
Cell Membrane Structures and Functions 47
PHOSPHOLIPID BILAYERS 47
MEMBRANE PROTEINS 50
BIOLOGICAL MEMBRANES 51
REFERENCES 57
Lipids 59
PROPERTIES OF BRAIN LIPIDS 59
COMPLEX LIPIDS 60
ANALYSIS OF BRAIN LIPIDS 64
BRAIN LIPID BIOSYNTHESIS 65
GENES FOR LIPID-SYNTHESIZING ENZYMES 70
LIPIDS IN THE CELLULAR MILIEU 72
REFERENCES 75
GENERAL REFERENCES 74
Myelin Formation, Structure and Biochemistry 77
THE MYELIN SHEATH 77
CHARACTERISTIC COMPOSITION OF MYELIN 82
DEVELOPMENTAL AND METABOLIC ASPECTS OF MYELIN 93
ACKNOWLEDGMENTS 96
REFERENCES 96
Membrane Transport 99
INTRODUCTION 99
PRIMARY ION TRANSPORTERS 100
Ca2+ PUMPS 105
V0V1- PROTON PUMPS 108
ATP-BINDING CASSETTES 108
SECONDARY ACTIVE TRANSPORT 110
PHYSIOLOGICAL ASPECTS OF THE NEUROTRANSMITTER TRANSPORTERS 112
CATION ANTIPORTERS 113
FACILITATORS 115
REFERENCES 117
Electrical Excitability and Ion Channels 121
MEMBRANE POTENTIALS AND ELECTRICAL SIGNALS IN EXCITABLE CELLS 121
ACTION POTENTIALS IN ELECTRICALLY EXCITABLE CELLS 124
FUNCTIONAL PROPERTIES OF VOLTAGE- GATED ION CHANNELS 125
THE VOLTAGE-GATED ION CHANNEL SUPERFAMILY 127
THE MOLECULAR BASIS FOR ION CHANNEL FUNCTION 129
ION CHANNEL DIVERSITY 133
ACKNOWLEDGMENTS 134
REFERENCES 134
Cell Adhesion Molecules 137
OVERVIEW 137
THE IMMUNOGLOBULIN GENE SUPERFAMILY 138
THE CADHERIN FAMILY 140
CELL ADHESION MOLECULES AND AXONAL OUTGROWTH 142
CELL ADHESION MOLECULES IN MYELINATION 144
SUMMARY 145
REFERENCES 146
The Cytoskeleton of Neurons and Glia 149
MOLECULAR COMPONENTS OF THE NEURONAL CYTOSKELETON 150
ULTRASTRUCTURE AND MOLECULAR ORGANIZATION OF NEURONS AND GLIA 157
CYTOSKELETAL STRUCTURES IN THE NEURON HAVE COMPLEMENTARY DISTRIBUTIONS AND FUNCTIONS 158
CONCLUSIONS 161
REFERENCES 161
Intracellular Trafficking 165
GENERAL MECHANISMS OF INTRACELLULAR MEMBRANE TRAFFICKING IN MAMMALIAN CELLS INCLUDE BOTH UNIVERSAL AND HIGHLY SPECIALIZED PROCESSES 165
FUNDAMENTALS OF MEMBRANE TRAFFICKING ARE BASED ON A SET OF COMMON PRINCIPLES 167
THE BIOSYNTHETIC SECRETORY PATHWAY INCLUDES SYNTHETIC, PROCESSING, TARGETING AND SECRETORY STEPS 170
THE ENDOCYTIC PATHWAY PLAYS MULTIPLE ROLES IN CELLS OF THE NERVOUS SYSTEM 177
SYNAPTIC VESICLE TRAFFICKING IS A SPECIALIZED FORM OF REGULATED SECRETION AND RECYCLING OPTIMIZED FOR SPEED AND EFFICIENCY 184
ACKNOWLEDGMENTS 188
REFERENCES 188
Intercellular Signaling 190
Synaptic Transmission and Cellular Signaling: An Overview 193
SYNAPTIC TRANSMISSION 193
CELLULAR SIGNALING MECHANISMS 203
ACKNOWLEDGMENTS 208
REFERENCES 208
Acetylcholine 211
CHEMISTRY OF ACETYLCHOLINE 212
ORGANIZATION OF THE CHOLINERGIC NERVOUS SYSTEM 212
FUNCTIONAL ASPECTS OF CHOLINERGIC NEUROTRANSMISSION 215
SYNTHESIS, STORAGE AND RELEASE OF ACETYLCHOLINE 218
ACETYLCHOLINESTERASE AND THE TERMINATION OF ACETYLCHOLINE ACTION 221
NICOTINIC RECEPTORS 223
MUSCARINIC RECEPTORS 229
REFERENCES 234
Catecholamines 237
INTRODUCTION 237
BIOSYNTHESIS OF CATECHOLAMINES 237
STORAGE AND RELEASE OF CATECHOLAMINES 239
ANATOMY OF CATECHOLAMINERGIC SYSTEMS 243
CATECHOLAMINE RECEPTORS 243
DOPAMINE RECEPTORS 244
ADRENERGIC RECEPTORS 246
DYNAMICS OF CATECHOLAMINE RECEPTORS 247
ACKNOWLEDGMENTS 249
REFERENCES 249
Serotonin 253
SEROTONIN, THE NEUROTRANSMITTER 253
SEROTONIN RECEPTORS 266
REFERENCES 273
Histamine 275
HISTAMINE: THE MESSENGER AND THE MOLECULE 275
HISTAMINERGIC CELLS OF THE CENTRAL NERVOUS SYSTEM: ANATOMY AND MORPHOLOGY 276
DYNAMICS OF HISTAMINE IN THE BRAIN 279
MOLECULAR SITES OF HISTAMINE ACTION 282
HISTAMINE ACTIONS ON THE NERVOUS SYSTEM 287
SIGNIFICANCE OF BRAIN HISTAMINE FOR DRUG ACTION 288
ACKNOWLEDGMENTS 289
REFERENCES 289
Glutamate 293
THE AMINO ACID GLUTAMATE IS THE MAJOR EXCITATORY NEUROTRANSMITTER IN THE BRAIN 294
BRAIN GLUTAMATE IS DERIVED FROM BLOOD- BORNE GLUCOSE AND AMINO ACIDS THAT CROSS THE BLOOD – BRAIN BARRIER 295
GLUTAMINE IS AN IMPORTANT IMMEDIATE PRECURSOR FOR GLUTAMATE: THE GLUTAMINE CYCLE 295
SYNAPTIC VESICLES ACCUMULATE TRANSMITTER GLUTAMATE BY VESICULAR GLUTAMATE TRANSPORTERS 296
IS ASPARTATE A NEUROTRANSMITTER? 297
LONG-TERM POTENTIATION OR DEPRESSION OF GLUTAMATERGIC SYNAPSES MAY UNDERLIE LEARNING 297
THE NEURONAL PATHWAYS OF THE HIPPOCAMPUS ARE ESSENTIAL STRUCTURES FOR MEMORY FORMATION 298
IONOTROPIC AND METABOTROPIC GLUTAMATE RECEPTORS ARE PRINCIPAL PROTEINS AT THE POSTSYNAPTIC DENSITY 299
THREE CLASSES OF IONOTROPIC GLUTAMATE RECEPTORS ARE IDENTIFIED 299
GLUTAMATE PRODUCES EXCITATORY POSTSYNAPTIC POTENTIALS 307
METABOTROPIC GLUTAMATE RECEPTORS MODULATE SYNAPTIC TRANSMISSION 308
GLUTAMATE RECEPTORS DIFFER IN THEIR POSTSYNAPTIC DISTRIBUTION 310
PROTEINS OF THE POSTSYNAPTIC DENSITY MEDIATE INTRACELLULAR EFFECTS OF GLUTAMATE RECEPTOR ACTIVATION 310
SMALL GTP-BINDING PROTEINS ( GTPases) MEDIATE CHANGES IN GENE EXPRESSION UPON NMDA RECEPTOR ACTIVATION 311
DENDRITIC SPINES ARE MOTILE, CHANGING THEIR SHAPE AND SIZE IN RESPONSE TO SYNAPTIC ACTIVITY WITHIN MINUTES 312
SODIUM-DEPENDENT SYMPORTERS IN THE PLASMA MEMBRANES CLEAR GLUTAMATE FROM THE EXTRACELLULAR SPACE 312
SODIUM-DEPENDENT GLUTAMINE TRANSPORTERS IN PLASMA MEMBRANES MEDIATE THE TRANSFER OF GLUTAMINE FROM ASTROCYTES TO NEURONS 313
EXCESSIVE GLUTAMATE RECEPTOR ACTIVATION MAY MEDIATE CERTAIN NEUROLOGICAL DISORDERS 313
REFERENCES 315
GABA and Glycine 317
GABA SYNTHESIS, UPTAKE AND RELEASE 317
GABA RECEPTOR PHYSIOLOGY AND PHARMACOLOGY 319
STRUCTURE AND FUNCTION OF GABA RECEPTORS 319
GLYCINE AS A CENTRAL NEUROTRANSMITTER: GLYCINE SYNTHESIS, UPTAKE AND DEGRADATION 324
GLYCINE RECEPTOR PHYSIOLOGY AND PHARMACOLOGY 324
GLYCINE RECEPTORS: STRUCTURE, PATHOLOGY AND LOCALIZATION 325
GABA AND GLYCINE ARE THE MAJOR RAPIDLY ACTING INHIBITORY NEUROTRANSMITTERS IN BRAIN 326
REFERENCES 326
Purinergic Systems 329
NOMENCLATURE OF PURINES AND PYRIMIDINES 329
PURINE RELEASE AND METABOLISM 329
PURINERGIC RECEPTORS 332
EFFECTS OF PURINES IN THE NERVOUS SYSTEM: ADENOSINE RECEPTORS 338
EFFECTS OF PURINES IN THE NERVOUS SYSTEM: ATP RECEPTORS 340
REFERENCES 341
Peptides 343
NEUROPEPTIDES 343
NEUROPEPTIDE RECEPTORS 352
NEUROPEPTIDE FUNCTIONS AND REGULATION 354
PEPTIDERGIC SYSTEMS IN DISEASE 356
REFERENCES 357
Intracellular Signaling 359
G Proteins 361
HETEROTRIMERIC G PROTEINS 361
SMALL G PROTEINS 368
OTHER FEATURES OF G PROTEINS 369
REFERENCES 370
Phosphoinositides 373
THE INOSITOL LIPIDS 373
THE INOSITOL PHOSPHATES 380
DIACYLGLYCEROL 382
PHOSPHOINOSITIDES AND CELL REGULATION 384
ACKNOWLEDGMENTS 385
REFERENCES 386
Cyclic Nucleotides in the Nervous System 387
INTRODUCTION: THE SECOND MESSENGER HYPOTHESIS 387
ADENYLYL CYCLASES 388
GUANYLYL CYCLASE 394
PHOSPHODIESTERASES 396
FUNCTIONAL ROLES FOR CYCLIC cAMP AND CYCLIC cGMP 401
FUTURE PERSPECTIVES 402
REFERENCES 402
Calcium 405
THE CONCEPT OF Ca2+ AS A CELLULAR SIGNAL 405
MEASUREMENT OF CELLULAR Ca2+ CONCENTRATIONS AND MOVEMENTS 405
Ca2+ REGULATION AT THE PLASMA MEMBRANE 406
Ca2+ STORES AND Ca2+ POOLS 407
Ca2+ SIGNALING 408
Ca2+-REGULATED PROCESSES 414
REFERENCES 415
Serine and Threonine Phosphorylation 417
PROTEIN PHOSPHORYLATION IS OF FUNDAMENTAL IMPORTANCE IN BIOLOGICAL REGULATION 417
PROTEIN SERINE–THREONINE KINASES 420
PROTEIN SERINE–THREONINE PHOSPHATASES 425
NEURONAL PHOSPHOPROTEINS 427
PROTEIN PHOSPHORYLATION MECHANISMS IN DISEASE 436
ACKNOWLEDGMENT 437
REFERENCES 437
Tyrosine Phosphorylation 441
TYROSINE PHOSPHORYLATION IN THE NERVOUS SYSTEM 441
PROTEIN TYROSINE KINASES 442
PROTEIN TYROSINE PHOSPHATASES 449
ROLE OF TYROSINE PHOSPHORYLATION IN THE NERVOUS SYSTEM 452
REFERENCES 458
Growth, Development and Differentiation 461
Development 463
FUNDAMENTAL CONCEPTS UNIFYING DEVELOPMENTAL DIVERSITY 463
GENERAL DEVELOPMENT OF THE NERVOUS SYSTEM 464
DEVELOPMENTAL PROCESSES: ENVIRONMENTAL FORCES MOLDING GENETIC POTENTIAL 466
MOLECULAR MECHANISMS OF DEVELOPMENT 468
CELL LINEAGES OF THE NERVOUS SYSTEM 475
CONCLUSIONS 483
REFERENCES 483
Transcription Factors in the Central Nervous System 485
THE TRANSCRIPTIONAL PROCESS 485
REGULATION OF TRANSCRIPTION BY TRANSCRIPTION FACTORS 487
GLUCOCORTICOID AND MINERALOCORTICOID RECEPTORS AS TRANSCRIPTION FACTORS 489
CYCLIC AMP REGULATION OF TRANSCRIPTION 492
TRANSCRIPTION AS A TARGET FOR DRUG DEVELOPMENT 495
REFERENCES 495
Growth Factors 497
GROWTH FACTORS ARE ESSENTIAL FOR NERVOUS SYSTEM DEVELOPMENT AND FUNCTION 497
CLASSES OF GROWTH FACTORS ACTING IN THE NERVOUS SYSTEM 499
GROWTH FACTORS ACT COMBINATORIALLY AND SEQUENTIALLY TO REGULATE NERVOUS SYSTEM DEVELOPMENT 509
REFERENCES 509
Axonal Transport 511
NEURONAL ORGANELLES IN MOTION 511
DISCOVERY AND CONCEPTUAL DEVELOPMENT OF FAST AND SLOW AXONAL TRANSPORT 512
FAST AXONAL TRANSPORT 514
SLOW AXONAL TRANSPORT 519
MOLECULAR MOTORS: KINESIN, DYNEIN AND MYOSIN 521
AXONAL TRANSPORT AND NEUROPATHOLOGY 525
CONCLUSION 525
ACKNOWLEDGMENTS 525
REFERENCES 525
Stem Cells in the Nervous System 529
STEM CELLS ARE MULTIPOTENT AND SELF- RENEWING 529
STEM CELLS CONTRIBUTE TO THE DEVELOPING NERVOUS SYSTEM 533
NEUROGENESIS OCCURS IN THE ADULT BRAIN 535
STEM CELLS OFFER THE POTENTIAL FOR REPAIR IN THE ADULT NERVOUS SYSTEM 536
STEM CELL TRANSPLANTS FOR NEURAL REPAIR 538
EXPANDING ENDOGENOUS NEURAL STEM CELLS FOR REPAIR 539
COMMON STEM CELL THERAPY CHALLENGES 540
CONCLUSIONS 540
REFERENCES 541
Axonal Growth in the Adult Mammalian Nervous System: Regeneration and Compensatory Plasticity 543
REGENERATION IN THE PERIPHERAL NERVOUS SYSTEM 544
REGENERATION IN THE CENTRAL NERVOUS SYSTEM 546
CENTRAL NERVOUS SYSTEM INJURY AND COMPENSATORY PLASTICITY 550
SUMMARY AND CONCLUSIONS 552
ACKNOWLEDGMENTS 552
REFERENCES 552
Metabolism 555
Energy Metabolism of the Brain 557
INTRODUCTION 558
SUBSTRATES FOR CEREBRAL ENERGY METABOLISM 559
AGE AND DEVELOPMENT INFLUENCE CEREBRAL ENERGY METABOLISM 561
REGULATION OF THE CEREBRAL METABOLIC RATE 562
METABOLISM IN THE BRAIN IS HIGHLY COMPARTMENTALIZED 563
GLYCOGEN IS ACTIVELY SYNTHESIZED AND DEGRADED IN BRAIN, PROVIDING A DYNAMIC SOURCE OF CARBOHYDRATE 564
GLYCOLYSIS: CONVERSION OF GLUCOSE TO PYRUVATE OR LACTATE 564
THE PENTOSE PHOSPHATE SHUNT IS ACTIVE IN BRAIN 566
GLYCEROL PHOSPHATE DEHYDROGENASE IS AN NADH OXIDIZING ENZYME RELATED TO GLYCOLYSIS 567
THE MALATE–ASPARTATE SHUTTLE HAS A KEY ROLE IN BRAIN METABOLISM 567
THERE IS DYNAMIC METABOLISM OF LACTATE IN BRAIN 568
THE COMPLETE OXIDATION OF GLUCOSE REQUIRES TRICARBOXYLIC ACID CYCLE ACTIVITY 569
ENERGY OUTPUT AND OXYGEN CONSUMPTION ARE ASSOCIATED WITH TCA CYCLE ACTIVITY 570
MANY TCA CYCLE ENZYMES AND COMPONENTS OF OXIDATIVE PHOSPHORYLATION ARE DIFFERENTIALLY DISTRIBUTED IN NEURONAL AND GLIAL MITOCHONDRIA 571
GLUTAMATE/GLUTAMINE METABOLISM IS LINKED TO ENERGY METABOLISM 573
HOW COMPARTMENTALIZED BRAIN METABOLISM IS STUDIED 575
RELATION OF ENERGY METABOLISM TO PATHOLOGICAL CONDITIONS IN THE BRAIN 578
ACKNOWLEDGMENT 578
REFERENCES 578
Hypoxic–Ischemic Brain Injury and Oxidative Stress 585
HYPOXIA–ISCHEMIA AND BRAIN INFARCTION 585
MICROVASCULAR INJURY IN HYPOXIA – ISCHEMIA 588
EXCITOTOXIC INJURY IN HYPOXIA – ISCHEMIA 589
ISCHEMIC APOPTOSIS 591
FREE RADICALS IN HYPOXIA– ISCHEMIA 592
NEUROPROTECTIVE STRATEGIES FOR HYPOXIC – ISCHEMIC INJURY 597
REFERENCES 597
Eicosanoids, Docosanoids, Platelet- Activating Factor and Infl ammation 601
STORAGE OF LIPID MESSENGERS IN NEURAL MEMBRANE PHOSPHOLIPIDS 602
PHOSPHOLIPASE A2 603
EICOSANOIDS 605
PLATELET-ACTIVATING FACTOR 605
CYCLOOXYGENASES 607
DIACYLGLYCEROL KINASES 610
LIPID SIGNALING PATHWAYS AND NEUROINFLAMMATION 610
DOCOSAHEXAENOIC ACID 612
LIPID PEROXIDATION AND OXIDATIVE STRESS 613
NEUROPROTECTIN D1: A DOCOSAHEXAENOIC-ACIDDERIVED MEDIATOR 613
THE FUTURE OF LIPID SIGNALING IN THE NERVOUS SYSTEM 613
REFERENCES 614
Metabolic Encephalopathies 620
BRAIN ENERGY METABOLISM 619
METABOLIC ENCEPHALOPATHY DUE TO LACK OF ENERGY SUBSTRATE 619
HYPONATREMIC ENCEPHALOPATHY 621
HYPERCAPNIC ENCEPHALOPATHY 622
METABOLIC ENCEPHALOPATHY DUE TO PERIPHERAL ORGAN FAILURE 622
THIAMINE DEFICIENCY (WERNICKE’S) ENCEPHALOPATHY 625
PYRIDOXINE (VITAMIN B6) DEFICIENCY 628
COBALAMIN (VITAMIN B12) DEFICIENCY 628
REFERENCES 628
Apoptosis and Necrosis 629
DISTINGUISHING FEATURES OF APOPTOSIS AND NECROSIS 629
APOPTOSIS 630
NECROSIS 639
TARGETING APOPTOSIS AND NECROSIS IN NEUROLOGICAL DISORDERS 640
REFERENCES 641
Inherited and Neurodegenerative Diseases 643
Peripheral Neuropathy 645
FEATURES COMMON TO THE PERIPHERAL AND CENTRAL NERVOUS SYSTEM IMPORTANT IN THE PATHOGENESIS AND PATHOPHYSIOLOGY OF NEUROPATHIES 646
FEATURES OF PERIPHERAL NERVES THAT INFLUENCE THEIR VULNERABILITY TO DISEASE AND CAPACITY FOR REGENERATION 646
PATHOGENESIS OF NEUROPATHIES 647
HEREDITARY AND ACQUIRED DISEASES INVOLVING THE ENTERIC NERVOUS SYSTEM 652
REFERENCES 652
The Epilepsies: Phenotype and Mechanisms 655
EPILEPSY IS A COMMON NEUROLOGICAL DISORDER 655
MECHANISMS OF ANTISEIZURE DRUGS 660
GENETICS OF EPILEPSY 661
REFERENCES 664
Diseases Involving Myelin 665
GENERAL CLASSIFICATION 665
ACQUIRED ALLERGIC AND/OR INFECTIOUS DISEASES OF MYELIN 666
GENETICALLY DETERMINED DISORDERS OF MYELIN 673
TOXIC AND NUTRITIONAL DISORDERS OF MYELIN DISORDERS PRIMARILY AFFECTING NEURONS WITH SECONDARY INVOLVEMENT OF MYELIN 675
REPAIR IN DEMYELINATING DISEASES 676
REFERENCES 677
Genetics of Neurodegenerative Diseases 679
GENETIC ASPECTS OF COMMON NEURODEGENERATIVE DISEASES 679
ALZHEIMER’S DISEASE 681
PARKINSON’S DISEASE 683
LEWY BODY DEMENTIA 685
FRONTOTEMPORAL DEMENTIA 685
AMYOTROPHIC LATERAL SCLEROSIS 687
NEURODEGENERATIVE TRIPLET REPEAT DISORDERS 687
CREUTZFELDT–JAKOB DISEASE AND OTHER PRION DISEASES 688
CONCLUDING REMARKS 689
REFERENCES 689
Disorders of Amino Acid Metabolism 693
INTRODUCTION 694
DISORDERS OF BRANCHED-CHAIN AMINO ACIDS: MAPLE SYRUP URINE DISEASE 697
DISORDERS OF PHENYLALANINE METABOLISM: PHENYLKETONURIA 698
DISORDERS OF GLYCINE METABOLISM: NONKETOTIC HYPERGLYCINEMIA 699
DISORDERS OF SULFUR AMINO ACID METABOLISM: HOMOCYSTINURIA 700
THE UREA CYCLE DEFECTS 704
DISORDERS OF GLUTATHIONE METABOLISM 707
DISORDERS OF 707
AMINOBUTYRIC 707
ACID METABOLISM 707
DISORDERS OF 708
ACETYL 708
ASPARTATE METABOLISM 708
REFERENCES 708
Lysosomal and Peroxisomal Diseases 711
LYSOSOMAL DISEASES 711
PEROXISOMAL DISORDERS 715
DIAGNOSIS OF LYSOSOMAL AND PEROXISOMAL DISORDERS 718
PATHOGENESIS OF LYSOSOMAL AND PEROXISOMAL DISORDERS 718
THERAPY OF LYSOSOMAL AND PEROXISOMAL DISORDERS 719
REFERENCES 719
Diseases of Carbohydrate, Fatty Acid and Mitochondrial Metabolism 721
DISEASES OF CARBOHYDRATE AND FATTY ACID METABOLISM IN MUSCLE 722
DISEASES OF CARBOHYDRATE AND FATTY ACID METABOLISM IN BRAIN 729
DISEASES OF MITOCHONDRIAL METABOLISM 732
ACKNOWLEDGMENTS 737
REFERENCES 737
Disorders of Muscle Excitability 739
ORGANIZATION OF THE NEUROMUSCULAR JUNCTION 739
EXCITATION AND CONTRACTION OF THE MUSCLE FIBER 742
GENETIC DISORDERS OF THE NEUROMUSCULAR JUNCTION 745
HEREDITARY DISEASES OF MUSCLE MEMBRANES 746
IMMUNE DISEASES OF MUSCLE EXCITABILITY 749
TOXINS AND METABOLITES THAT ALTER MUSCULAR EXCITATION 751
REFERENCES 755
Motor Neuron Diseases 757
AMYOTROPHIC LATERAL SCLEROSIS IS THE MOST COMMON ADULT ONSET MOTOR NEURON DISEASE 757
NON-TRANSGENIC, INDUCED MODELS OF MOTOR NEURON DISEASE 760
SELECTED GENETIC MODELS OF RELEVANCE TO AMYOTROPHIC LATERAL SCLEROSIS 761
ACKNOWLEDGMENTS 765
REFERENCES 765
Neurodegenerative Synucleinopathies and Tauopathies 771
THE SYNUCLEIN FAMILY 772
PARKINSON’S DISEASE AND OTHER LEWY BODY DISEASES 773
MULTIPLE SYSTEM ATROPHY 775
SYNTHETIC 776
SYNUCLEIN FILAMENTS 776
ANIMAL MODELS OF HUMAN 776
SYNUCLEINOPATHIES 776
SYNUCLEINOPATHIES— 777
OUTLOOK 777
TAU ISOFORMS AND THEIR INTERACTIONS WITH MICROTUBULES 777
TAU AND ALZHEIMER’S DISEASE 778
SPORADIC TAUOPATHIES 779
MUTATIONS CAUSING TAUOPATHY— THE FTDP- 17 SYNDROMES 780
RELEVANCE FOR THE SPORADIC TAUOPATHIES 781
SYNTHETIC TAU FILAMENTS 781
ANIMAL MODELS OF HUMAN TAUOPATHIES 782
TAUOPATHIES — OUTLOOK 783
REFERENCES 784
Neurotransmitters and Disorders of the Basal Ganglia 787
ANATOMY AND PHYSIOLOGY OF THE BASAL GANGLIA 787
DISORDERS THAT INVOLVE BASAL GANGLIA DYSFUNCTION 792
REFERENCES 803
Neurobiology of Alzheimer’s Disease 807
ALZHEIMER’S DISEASE IS THE MOST PREVALENT NEURODEGENERATIVE DISORDER 807
ACKNOWLEDGMENTS 813
REFERENCES 813
Molecular Basis of Prion Diseases 817
INTRODUCTION 817
PRION DISEASES ARE BIOLOGICALLY UNIQUE 818
ANIMAL PRION DISEASES 818
HUMAN PRION DISEASES 819
PRION DISEASE PATHOLOGY AND PATHOGENESIS 820
THE PROTEIN-ONLY HYPOTHESIS OF PRION PROPAGATION 821
CHARACTERIZATION OF PrPC 822
CHARACTERIZATION OF PrPSC 823
THE MOLECULAR BASIS OF PRION STRAIN DIVERSITY 825
PRION TRANSMISSION BARRIERS 826
CELL DEATH IN PRION DISEASE 827
FUTURE PERSPECTIVES 828
REFERENCES 828
Sensory Transduction 831
Molecular Biology of Vision 833
PHYSIOLOGICAL BACKGROUND 833
PHOTORECEPTOR MEMBRANES AND VISUAL PIGMENTS 835
PHOTOTRANSDUCTION 838
COLOR BLINDNESS RETINITIS PIGMENTOSA 840
AGE-RELATED MACULAR DEGENERATION 841
REFERENCES 841
Molecular Biology of Olfaction and Taste 843
OLFACTION 843
TASTE 851
ACKNOWLEDGMENTS 855
REFERENCES 855
Molecular Biology of Hearing and Balance 859
GENERAL FEATURES OF MECHANORECEPTORS 859
MODEL SYSTEMS 860
HAIR CELLS 861
DEAFNESS 865
CONCLUSIONS 866
REFERENCES 866
Neural Processing and Behavior 867
Endocrine Effects on the Brain and Their Relationship to Behavior 869
INTRODUCTION 869
BEHAVIORAL CONTROL OF HORMONAL SECRETION 870
CLASSIFICATION OF HORMONAL EFFECTS 872
BIOCHEMISTRY OF STEROID AND THYROID HORMONE ACTIONS 873
INTRACELLULAR STEROID RECEPTORS: PROPERTIES AND TOPOGRAPHY 877
MEMBRANE STEROID RECEPTORS AND SIGNALING PATHWAYS 878
BIOCHEMISTRY OF THYROID HORMONE ACTIONS ON BRAIN 879
DIVERSITY OF STEROID-HORMONE ACTIONS ON THE BRAIN 880
REFERENCES 883
Learning and Memory 885
BRIEF HISTORY OF MEMORY RESEARCH IN HUMANS 885
DIVISIONS OF MEMORY 887
MOLECULAR MECHANISMS OF LEARNING 887
MOLECULAR MECHANISMS OF MEMORY CONSOLIDATION AND STORAGE 893
FUTURE DIRECTIONS AND CHALLENGES 898
REFERENCES 899
The Neurochemistry of Schizophrenia 901
CLINICAL ASPECTS OF SCHIZOPHRENIA 901
BRAIN IMAGING 904
CELLULAR AND MOLECULAR STUDIES 906
CONCLUSION 910
REFERENCES 910
Neurobiology of Severe Mood and Anxiety Disorders 913
MOOD DISORDERS 914
NEUROTRANSMITTER AND NEUROPEPTIDE SYSTEMS ARE IMPLICATED IN THE PATHOPHYSIOLOGY OF BIPOLAR AND MAJOR DEPRESSIVE DISORDERS 915
ABNORMALITIES OF SLEEP RHYTHMS IN MOOD DISORDERS 920
NEUROANATOMICAL AND NEUROPATHOLOGICAL CORRELATES OF MOOD DISORDERS 920
STRESS, GLUCOCORTICOIDS AND NEUROPLASTICITY IN THE PATHOLOGY OF MOOD DISORDERS 921
INTRACELLULAR SIGNALING PATHWAYS INTEGRATE ENVIRONMENTAL AND GENETIC CUES INVOLVED IN MOOD 921
INTRACELLULAR CALCIUM SIGNALING STUDIES IN BIPOLAR DISORDER 925
ANXIETY DISORDERS 925
INTRACELLULAR TARGETS FOR ANXIETY DISORDERS 930
FUTURE DIRECTIONS AND THE DEVELOPMENT OF NOVEL THERAPEUTICS 931
REFERENCES 931
Addiction 937
GENERAL PRINCIPLES 937
NEURONAL CIRCUITRY OF ADDICTION 938
OPIATES 940
PSYCHOMOTOR STIMULANTS 942
CANNABINOIDS (MARIJUANA) 945
NICOTINE 947
ETHANOL, SEDATIVES AND ANXIOLYTICS 948
HALLUCINOGENS AND DISSOCIATIVE DRUGS 949
ADDICTION AND NEURONAL PLASTICITY SHARE COMMON CELLULAR MECHANISMS 949
ACKNOWLEDGMENTS 950
REFERENCES 951
Pain 953
INTRODUCTION: THE PAIN PATHWAY 953
PRIMARY SENSORY NEURONS 954
DORSAL HORN 956
THE BRAIN 957
CLINICAL PAIN 958
INFLAMMATORY PAIN 959
NEUROPATHIC PAIN 961
CONCLUSION 963
REFERENCES 963
Neuroimaging 965
MAGNETIC RESONANCE IMAGING ( MRI) 966
MAGNETIC RESONANCE SPECTROSCOPY ( MRS) 968
POSITRON EMISSION TOMOGRAPHY ( PET) AND SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY ( SPECT) 970
APPLICATIONS OF PET AND SPECT FOR BRAIN FUNCTION 971
CNS DRUG DESIGN AND PRECLINICAL/ CLINICAL DRUG DEVELOPMENT 974
CLINICAL APPLICATIONS OF PET AND SPECT 975
APPENDIX 976
REFERENCES 983
Glossary 989
Index 995